Potent Benzodiazepine Antagonist Activity

Abstract

U-78875 (3-(5-cyclopropyl-1,2,4-oxadiarol-3-yl)-5-(1-methyleth-yI)imidazo[1,5-aJ-quinoxalin-4(5H)-one) is a chemically novel compound with a high affinity for the benzodiazepine receptors. It has anticonflict effects in both the Vogel and Cook-Davidson models of anxiety, with a potency similar to that of diazepam (1-3 mg/kg, i.p.). In unanesthetized rats implanted with cortical electrodes for EEG recording, i.p. injections of U-78875 (3-10 mg/kg) increased the EEG power density in frequencies above I 2 Hz, and decreased EEG power at lower frequencies. This EEG effect is similar to that of diazepam, and was completely antagonized by pretreatment with fiumazenil. In animal models measuring central nervous system depression, U-78875 is much weaker than diazepam. It produced minimal impairment of ro-tarod performance in rats at doses up to 30 mg/kg, but at lowe